Juvenile colon cancer diagnosed by onset of intussusception: a case report suggestive of Lynch syndrome treated with laparoscopic colectomy

Juvenile colon cancer diagnosed by onset of intussusception: a case report suggestive of Lynch syndrome treated with laparoscopic colectomy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Juvenile colon cancer diagnosed by onset of intussusception: a case report suggestive of Lynch syndrome treated with laparoscopic colectomy Ryosuke Ogata, Toshiyuki Fujii, Keisuke Hino, Ryouichi Tsunedomi, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2725014/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : One characteristic of Lynch syndrome, which is caused by germline mutations in a group of genes encoding mismatch repair proteins, is the early onset of colorectal cancer. Here, we report a rare case of juvenile colon cancer, diagnosed based on the onset of intussusception with high microsatellite instability (MSI) and the absence of BRAF mutations, which was suggestive of Lynch syndrome. Case presentation : A 28-year-oldman presented with right lower abdominal pain for approximately 3 months and defecated blacky stool for several weeks. He visited our hospital because of increasingly intense right lower abdominal pain. Computed tomography revealed a contrast-enhanced tumor and lymph nodes with a crab-claw-like fitted image extending into the ascending colon. Colon endoscopy revealed a large submucosal tumor-like lesion with ulceration. Laparoscopy-assisted ileal resection with level 3 lymph node dissection was performed 3 days after the endoscopic reduction of the intussusception. The histological diagnosis was a poorly differentiated adenocarcinoma. Gene analysis of the resected tumor revealed high MSIand KRAS mutations, and the absence of BRAF mutations. Immunohistochemistry indicated the absence of MLH1 and PMS2 expression in tumors. Genetic analysis of peripheral blood and tumors revealed no pathological mutations in MLH1, MSH2, PMS2, or MSH6. Conclusion A rare case of Lynch-like syndrome was diagnosed with intussusception. MSI-high, wild-type BRAF, and the absence of MLH1 and PMS2 expression suggested Lynch syndrome. The absence of pathological mutations in germline and somatic genes suggests the possibility of MLH1 promoter methylation or MLH1 epimutation in the pathogenesis of this case. Lynch syndrome microsatellite instability BRAF juvenile colon cancer intussusception laparoscopic colectomy Figures Figure 1 Figure 2 Figure 3 Figure 4 Background In adults, intussusception is relatively rare, accounting for approximately 5% of all intussusception cases. Cancer is the most common cause of intussusception, occurring in the colon in approximately 60% of cases [ 1 ] [ 2 ]. There is no clear definition of the age of juvenile colorectal cancer but it is often defined as 40 years of age or younger. According to the Japanese National Cancer Institute in 2015, 1.15% of all patients with colorectal cancer are under 40 years of age and 0.10% are aged 25–29[ 3 ]. Causes of juvenile-onset colorectal cancer include Lynch syndrome, familial colorectal adenomatosis, and hereditary breast-ovarian cancer syndrome. Lynch syndrome is an autosomal dominant disorder caused by germline mutations in a gene cluster that encodes mismatch repair (MMR) proteins [ 4 ]. When the MMR function is defective, errors made during DNA replication are not repaired and may accumulate, leading to cancer. This phenomenon is known as microsatellite instability (MSI). Therefore, MSI testing for malignant tumors and immunohistochemical testing for MMR proteins may be useful for diagnosing Lynch syndrome. Lynch syndrome was diagnosed by confirming that the Amsterdam and Bethesda criteria [ 5 ] are met (primary screening), followed by MSI or immunohistological testing (secondary screening) [ 6 ] [ 7 ]. If abnormalities are detected in secondary screening, genetic diagnosis using the germline of the MMR gene, such as MutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 2 (PMS2), mutS homolog 6 (MSH6), is performed; the detection of pathological mutations is the basis of a definitive diagnosis of Lynch syndrome [ 8 ]. Lynch syndrome is often MSI-high and characterized by the absence of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation [ 9 ]. Colorectal cancer associated with Lynch syndrome is characterized by a relatively good prognosis, despite the fact that histology often shows poorly differentiated adenocarcinoma and mucinous carcinoma [ 10 ]. We encountered a case of colorectal cancer in a young patient, whose diagnosis was triggered by the onset of intussusception. Genetic analysis strongly suggested Lynch syndrome because of MSI-high and BRAF mutation-negative results. There are few reports of Lynch syndrome or Lynch-like syndrome diagnosed at the onset of intussusception. Here, we report a case of Lynch-like syndrome diagnosed at the onset of intussusception. Case Presentation The patient, who visited the Gastroenterology Center of Shunan Memorial Hospital, was a 28-year-old male who had been experiencing right lower abdominal pain for approximately 3 months. He had also defecated black stools for several weeks. His medical history included gastric ulcers during his teens. There was no significant family history of cancer, including colorectal cancer. A physical examination revealed tenderness and rebound pain in the right lower abdomen. Blood tests revealed no liver or renal function problems, and a microcytic iron deficient anemia. His hemoglobin level was 10.4 g/dL and serum Fe level was 15 micro g/dL. Tumor markers were analyzed but soluble interleukin-2 receptor (sIL2R), carcinoembryonic antigen (CEA), and carbohydrate antigen 19 − 9 (CA19-9) levels were within normal ranges. Abdominal ultrasonography showed that the target sign was superimposed on the ascending colon to the transverse colon at the hepatic flexure (Fig. 1 a). Computed tomography (CT) revealed concentric circles of invagination in the intestine fitting into the ascending colon (Fig. 1 b), with the terminal portion of the ileum as the advanced portion (Fig. 1 c). The regional lymph nodes were enlarged (Fig. 1 d). An emergency lower endoscopy was performed for diagnosis, which resulted in the treatment of the invagination and revealed a large submucosal tumor-like lesion with ulceration in the cecum (Fig. 2 a). Contrast enema revealed a shadow defect in the cecum (Fig. 2 b). Based on these results, malignant lymphoma, gastrointestinal stromal tumor (GIST), and colon cancer were considered in the differential diagnosis. Laparoscopic ileocecal resection with D3 lymph node dissection was performed, and the patient was discharged after surgery. The tumor was type 3 and 50 × 40 mm (Fig. 3 a), and pathological findings showed that it was mainly an intermediately differentiated adenocarcinoma with some components of poorly differentiated adenocarcinoma. Infiltrating lymphocytes were also observed (Fig. 3 b). There was a mucus-producing component within the tumor, which was a characteristic of mucinous carcinoma (Fig. 3 c). The tumor invaded the subserosa (pT3), and there was no evidence of lymph node metastasis (pN0) or distant metastasis (M0). Gene analysis of the tumor revealed a v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (G13D), wild-type BRAF, and MSI-high. This case of juvenile colon cancer, with no lymph node metastasis, wild-type BRAF, MSI-high, and some components of poorly differentiated adenocarcinoma in the histological findings, strongly suggests Lynch syndrome. Immunohistochemistry was performed for MLH1, MSH2, PMS2, and MSH6, and sections were incubated with anti-MLH1 antibody (mouse monoclonal antibody, M1, Roche Diagnostics, Tokyo, Japan), anti-MSH2 antibody (mouse monoclonal antibody, G219-1129, Roche Diagnostics), anti-PMS2 antibody (mouse monoclonal antibody, A16-4, Roche Diagnostics), and anti-MSH6 antibody (rabbit monoclonal antibody, SP93, Roche Diagnostics). Immunohistochemistry revealed the absence of MLH1 and PMS2 in the nuclei of colon cancer cells (Fig. 4 a–d). Whole exome sequencing (WES) was performed using DNA from peripheral blood and tumors as previously described [ 11 ]. WES revealed germline mutations in PMS2 (rs2228006, c.1621A > G), PMS2 (rs1805321, c.1408C > T), and MSH2 (rs63750716, c.505A > G), which were not pathogenic. The somatic mutation in MSH6 (NM_000179.2|c. 2780T > C) was also not pathogenic. These analysis were conducted according to the Declaration of Helsinki and was approved by the Institutional Ethics Review Boards of Shunan Memorial Hospital (04–07) and Yamaguchi University (approval no. H17-83). Discussion Here, we report a rare case of Lynch-like syndrome diagnosed at the onset of intussusception. Only three cases with the same pathological condition have been reported [ 12 ] [ 13 ] [ 14 ]. Another case of intussusception caused by colon cancer in a young adult has been reported; however, no genetic examination was performed for the diagnosis of Lynch syndrome [ 15 ]. If a young person has colorectal cancer, close examination for Lynch syndrome should be performed. Although the results of the genetic tests indicated the possibility of Lynch syndrome in this juvenile colon cancer case, the family history did not meet the Amsterdam and Bezesta criteria [ 5 ]. We examined the immunohistochemical patterns and exome sequences of MLH1, MSH2, PMS2, and MSH6. IHC indicated the absence of MLH1 and PMS2 expression in the tumors. These data suggest the loss of MLH1 function because the expression of PMS2 depends on the availability of MLH1 function [ 16 ]. In contrast, genetic analysis of the peripheral blood and tumor revealed no pathological mutations in MLH1, MSH2, PMS2, or MSH6. Germline mutations in MMR-related genes cannot be identified in 10–15% of patients with clinically suspected Lynch syndrome; thus, Lynch-like syndrome has been proposed for patients with colorectal cancer who are MSI-H but do not have germline mutations in MMR genes [ 17 ]. We suggest that this patient had MLH1 promoter methylation or MLH1 epimutation [ 18 ]. Lynch syndrome has been suggested to have a better prognosis than sporadic colorectal cancer. One reason for this is the low proportion of patients with advanced-stage Lynch syndrome. In stages I, II, and III, the survival rate of MSI-high colorectal cancer is significantly higher in stage I, II, and III microsatellite stable colorectal cancer [ 19 ]. Therefore, the patient did not receive adjuvant chemotherapy. Conclusion We encountered a rare case of Lynch–like syndrome in which the diagnosis was based on the onset of intussusception. MSI-high, wild-type BRAF, and the absence of MLH1 and PMS2 expression suggested Lynch syndrome. Additionally, there were no pathological mutations in the germline or somatic gene sequence. Hence, we suggest the possibility of MLH1 promoter methylation or MLH1 epimutation in the pathogenesis of this case. Abbreviations MMR：mismatch repair MSI：microsatellite instability BRAF：v-raf murine sarcoma viral oncogene homolog B1 KRAS：v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog CT：Computed tomography sIL2R：soluble interleukin-2 receptor CEA：carcinoembryonic antigen CA19-9：carbohydrateantigen 19-9 GIST： gastrointestinal stromal tumor Declarations Ethics approval and consent to participate These analyses were conducted according to the Declaration of Helsinki and was approved by the Institutional Ethics Review Boards of Shunan Memorial Hospital (04-07) and Yamaguchi University (approval no. H17-83). Consent for publication Written informed consent was obtained from the patients for publication of this report and any accompanying analyses. Availability of data and materials All data generated or analyzed for this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding Not applicable Authors' contributions RO, TF, and SH performed the treatment of the patient. RO, SH, and KH collected the clinical data and wrote the manuscript. SH, RO, KH, RT, HN, TN applied and assessed the results of genetic examination and discussed the obtained results. TI, TK, RO, and SH applied and assessed the results of immunohistochemical examination and discussed the obtained results. All authors attended the discussion, and all authors have read and approved the final manuscript. Acknowledgements Not applicable References Nagorney DM, Sarr MG, McIlrath DC: Surgical management of intussusception in the adult . Ann Surg 1981, 193 :230-236. Siow SL, Chea CH, Hashimah AR, Ting SC: Adult intussusception: 5-year experience in Sarawak . Med J Malaysia 2011, 66 :199-201. https://ganjoho.jp/reg_stat/statistics/data/dl/index.html#a14 . 2015. Lynch HT, de la Chapelle A: Hereditary colorectal cancer . N Engl J Med 2003, 348 :919-932. Lipton LR, Johnson V, Cummings C, Fisher S, Risby P, Eftekhar Sadat AT, Cranston T, Izatt L, Sasieni P, Hodgson SV et al : Refining the Amsterdam Criteria and Bethesda Guidelines: testing algorithms for the prediction of mismatch repair mutation status in the familial cancer clinic . J Clin Oncol 2004, 22 :4934-4943. Vasen HF, Watson P, Mecklin JP, Lynch HT: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC . Gastroenterology 1999, 116 :1453-1456. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R et al : Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability . J Natl Cancer Inst 2004, 96 :261-268. Peltomaki P: Lynch syndrome genes . Fam Cancer 2005, 4 :227-232. Thiel A, Heinonen M, Kantonen J, Gylling A, Lahtinen L, Korhonen M, Kytola S, Mecklin JP, Orpana A, Peltomaki P et al : BRAF mutation in sporadic colorectal cancer and Lynch syndrome . Virchows Arch 2013, 463 :613-621. Sinicrope FA: Lynch Syndrome-Associated Colorectal Cancer . N Engl J Med 2018, 379 :764-773. Kanesada K, Tsunedomi R, Hazama S, Ogihara H, Hamamoto Y, Shindo Y, Matsui H, Tokumitsu Y, Yoshida S, Iida M et al : Association between a single nucleotide polymorphism in the R3HCC1 gene and irinotecan toxicity . Cancer Med 2023, 12 :4294-4305. Omachi R, Kojima M, Miyake T, Ueki T, Iida H, Yamaguchi T, Ishikawa K, Kaida S, Takebayashi K, Maehira H et al : [A Case of Intussusception Due to Juvenile Colorectal Cancer with Suspected Lynch Syndrome] . Gan To Kagaku Ryoho 2021, 48 :2145-2147. McLeod KG, Balasuriya HD, Hodder RJ: Unusual case of intussuscepting right colon cancer in a 21-year-old with Lynch syndrome . ANZ J Surg 2021, 91 :E413-E414. Wright JP, Monson JRT, Albert MR: Lynch Syndrome Diagnosed During Pregnancy Presenting as Acute Ileocolic Intussusception in the Third Trimester . Am Surg 2023, 89 :165-167. Katayama S, Watanabe M, Miyake T, Mikane Y, Syoji R, Kajiwara Y, Konishi D, Tabuchi M, Aoyama K, Nogami T et al : [A Case of Intussusception Caused by Colon Cancer in A 25-Year-Old Woman] . Gan To Kagaku Ryoho 2017, 44 :1248-1250. Abildgaard AB, Nielsen SV, Bernstein I, Stein A, Lindorff-Larsen K, Hartmann-Petersen R: Lynch syndrome, molecular mechanisms and variant classification . Br J Cancer 2023, 128 :726-734. Kang SY, Park CK, Chang DK, Kim JW, Son HJ, Cho YB, Yun SH, Kim HC, Kwon M, Kim KM: Lynch-like syndrome: characterization and comparison with EPCAM deletion carriers . Int J Cancer 2015, 136 :1568-1578. Zyla R, Graham T, Aronson M, Velsher L, Mrkonjic M, Turashvili G: MLH1 epimutation is a rare mechanism for Lynch syndrome: A case report and review of the literature . Genes Chromosomes Cancer 2021, 60 :635-639. Stigliano V, Assisi D, Cosimelli M, Palmirotta R, Giannarelli D, Mottolese M, Mete LS, Mancini R, Casale V: Survival of hereditary non-polyposis colorectal cancer patients compared with sporadic colorectal cancer patients . J Exp Clin Cancer Res 2008, 27 :39. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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00:44:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2725014/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2725014/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":35124917,"identity":"341069a5-e35f-4c2b-b527-37ef85757006","added_by":"auto","created_at":"2023-03-31 21:41:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":386253,"visible":true,"origin":"","legend":"\u003cp\u003ePreoperative radiographies.\u003c/p\u003e\n\u003cp\u003ea. Abdominal ultrasonography revealing a target sign (white arrow) and suspected intestinal intussusception.\u003c/p\u003e\n\u003cp\u003eb. The cross section of abdominal CT showed concentric findings of overlapping\u003c/p\u003e\n\u003cp\u003eintestinal tract (white arrow) fits into the colon at the advanced end of the ileum.\u003c/p\u003e\n\u003cp\u003ec. A sagittal section of the computed tomography (CT) scan revealed intestinal intussusception with the ascending colon as the advanced part.\u003c/p\u003e\n\u003cp\u003ed. The sagittal section of CT scan finding the regional lymph nodes were enlarged.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2725014/v1/3e561cc5778cfaa563de5bb8.png"},{"id":35124918,"identity":"24492a08-b575-4c0a-89f3-35d5ed95ebfa","added_by":"auto","created_at":"2023-03-31 21:41:19","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":167542,"visible":true,"origin":"","legend":"\u003cp\u003eFindings during lower endoscopy\u003c/p\u003e\n\u003cp\u003ea. Lower endoscopy revealed a large submucosal tumor-like lesion with ulceration.\u003c/p\u003e\n\u003cp\u003eb. Gastrointestinal angiography showed a shadow defect in the tumor area (white arrow).\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2725014/v1/93903bce968503492ea61047.jpg"},{"id":35124919,"identity":"c01c0482-1b04-4b4c-9dfc-1d1d26848b46","added_by":"auto","created_at":"2023-03-31 21:41:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":482646,"visible":true,"origin":"","legend":"\u003cp\u003ePathological findings\u003c/p\u003e\n\u003cp\u003ea. Macroscopic findings of the resected specimen of the colon. A type 3 mass is seen in the cecum. Ulcer-infiltrating tumor, 50 mm x 40 mm in size.\u003c/p\u003e\n\u003cp\u003eb. Histopathological findings of resected colon showed some components of poorly differentiated adenocarcinoma with massive lymphocytes infiltrating into the peri-tumor.\u003c/p\u003e\n\u003cp\u003ec. There is a mucus-producing component within the tumor, which is a finding of mucinous carcinoma (white arrow).\u003c/p\u003e","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-2725014/v1/5486541795abd2da92b4fb61.png"},{"id":35124920,"identity":"6656daf1-047b-4ec0-910b-68873fdafc41","added_by":"auto","created_at":"2023-03-31 21:41:19","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":494821,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical pattern: MLH1, MSH2, PMS2, MSH6\u003c/p\u003e\n\u003cp\u003eImmunohistochemistry results, indicating the absence of MLH1 and PMS2 expression in the nuclei of colon cancer cells. Stromal cells, such as immune cells, stain positive\u003c/p\u003e\n\u003cp\u003ea. MLH1 proteins are absent. b. MSH2 proteins are present. c. PMS2 proteins are absent. d. MSH6 proteins are present.\u003c/p\u003e","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-2725014/v1/945c0158ec35deba36b1a5c1.png"},{"id":35126150,"identity":"0eb4b484-cc77-4bac-a48d-a81a8cae512d","added_by":"auto","created_at":"2023-03-31 21:49:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4775531,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2725014/v1/590e3f3c-ffe1-47cf-9fa4-04cfd5471a54.pdf"},{"id":35126149,"identity":"0f295347-24a3-478e-b377-728bb6fe03e8","added_by":"auto","created_at":"2023-03-31 21:49:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4775531,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2725014/v1/31337e64-39fb-4d24-b76d-7516064b5704.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Juvenile colon cancer diagnosed by onset of intussusception: a case report suggestive of Lynch syndrome treated with laparoscopic colectomy","fulltext":[{"header":"Background","content":"\u003cp\u003eIn adults, intussusception is relatively rare, accounting for approximately 5% of all intussusception cases. Cancer is the most common cause of intussusception, occurring in the colon in approximately 60% of cases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere is no clear definition of the age of juvenile colorectal cancer but it is often defined as 40 years of age or younger. According to the Japanese National Cancer Institute in 2015, 1.15% of all patients with colorectal cancer are under 40 years of age and 0.10% are aged 25\u0026ndash;29[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Causes of juvenile-onset colorectal cancer include Lynch syndrome, familial colorectal adenomatosis, and hereditary breast-ovarian cancer syndrome.\u003c/p\u003e \u003cp\u003eLynch syndrome is an autosomal dominant disorder caused by germline mutations in a gene cluster that encodes mismatch repair (MMR) proteins [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. When the MMR function is defective, errors made during DNA replication are not repaired and may accumulate, leading to cancer. This phenomenon is known as microsatellite instability (MSI). Therefore, MSI testing for malignant tumors and immunohistochemical testing for MMR proteins may be useful for diagnosing Lynch syndrome. Lynch syndrome was diagnosed by confirming that the Amsterdam and Bethesda criteria [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] are met (primary screening), followed by MSI or immunohistological testing (secondary screening) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. If abnormalities are detected in secondary screening, genetic diagnosis using the germline of the \u003cem\u003eMMR\u003c/em\u003e gene, such as MutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 2 (PMS2), mutS homolog 6 (MSH6), is performed; the detection of pathological mutations is the basis of a definitive diagnosis of Lynch syndrome [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Lynch syndrome is often MSI-high and characterized by the absence of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Colorectal cancer associated with Lynch syndrome is characterized by a relatively good prognosis, despite the fact that histology often shows poorly differentiated adenocarcinoma and mucinous carcinoma [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe encountered a case of colorectal cancer in a young patient, whose diagnosis was triggered by the onset of intussusception. Genetic analysis strongly suggested Lynch syndrome because of MSI-high and BRAF mutation-negative results. There are few reports of Lynch syndrome or Lynch-like syndrome diagnosed at the onset of intussusception. Here, we report a case of Lynch-like syndrome diagnosed at the onset of intussusception.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eThe patient, who visited the Gastroenterology Center of Shunan Memorial Hospital, was a 28-year-old male who had been experiencing right lower abdominal pain for approximately 3 months. He had also defecated black stools for several weeks. His medical history included gastric ulcers during his teens. There was no significant family history of cancer, including colorectal cancer.\u003c/p\u003e \u003cp\u003eA physical examination revealed tenderness and rebound pain in the right lower abdomen. Blood tests revealed no liver or renal function problems, and a microcytic iron deficient anemia. His hemoglobin level was 10.4 g/dL and serum Fe level was 15 micro g/dL. Tumor markers were analyzed but soluble interleukin-2 receptor (sIL2R), carcinoembryonic antigen (CEA), and carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (CA19-9) levels were within normal ranges.\u003c/p\u003e \u003cp\u003eAbdominal ultrasonography showed that the target sign was superimposed on the ascending colon to the transverse colon at the hepatic flexure (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Computed tomography (CT) revealed concentric circles of invagination in the intestine fitting into the ascending colon (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb), with the terminal portion of the ileum as the advanced portion (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). The regional lymph nodes were enlarged (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAn emergency lower endoscopy was performed for diagnosis, which resulted in the treatment of the invagination and revealed a large submucosal tumor-like lesion with ulceration in the cecum (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). Contrast enema revealed a shadow defect in the cecum (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Based on these results, malignant lymphoma, gastrointestinal stromal tumor (GIST), and colon cancer were considered in the differential diagnosis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eLaparoscopic ileocecal resection with D3 lymph node dissection was performed, and the patient was discharged after surgery. The tumor was type 3 and 50 \u0026times; 40 mm (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea), and pathological findings showed that it was mainly an intermediately differentiated adenocarcinoma with some components of poorly differentiated adenocarcinoma. Infiltrating lymphocytes were also observed (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). There was a mucus-producing component within the tumor, which was a characteristic of mucinous carcinoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec). The tumor invaded the subserosa (pT3), and there was no evidence of lymph node metastasis (pN0) or distant metastasis (M0). Gene analysis of the tumor revealed a v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (G13D), wild-type BRAF, and MSI-high. This case of juvenile colon cancer, with no lymph node metastasis, wild-type BRAF, MSI-high, and some components of poorly differentiated adenocarcinoma in the histological findings, strongly suggests Lynch syndrome.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eImmunohistochemistry was performed for MLH1, MSH2, PMS2, and MSH6, and sections were incubated with anti-MLH1 antibody (mouse monoclonal antibody, M1, Roche Diagnostics, Tokyo, Japan), anti-MSH2 antibody (mouse monoclonal antibody, G219-1129, Roche Diagnostics), anti-PMS2 antibody (mouse monoclonal antibody, A16-4, Roche Diagnostics), and anti-MSH6 antibody (rabbit monoclonal antibody, SP93, Roche Diagnostics). Immunohistochemistry revealed the absence of MLH1 and PMS2 in the nuclei of colon cancer cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea\u0026ndash;d).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWhole exome sequencing (WES) was performed using DNA from peripheral blood and tumors as previously described [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. WES revealed germline mutations in PMS2 (rs2228006, c.1621A\u0026thinsp;\u0026gt;\u0026thinsp;G), PMS2 (rs1805321, c.1408C\u0026thinsp;\u0026gt;\u0026thinsp;T), and MSH2 (rs63750716, c.505A\u0026thinsp;\u0026gt;\u0026thinsp;G), which were not pathogenic. The somatic mutation in MSH6 (NM_000179.2|c. 2780T\u0026thinsp;\u0026gt;\u0026thinsp;C) was also not pathogenic.\u003c/p\u003e \u003cp\u003eThese analysis were conducted according to the Declaration of Helsinki and was approved by the Institutional Ethics Review Boards of Shunan Memorial Hospital (04\u0026ndash;07) and Yamaguchi University (approval no. H17-83).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHere, we report a rare case of Lynch-like syndrome diagnosed at the onset of intussusception. Only three cases with the same pathological condition have been reported [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Another case of intussusception caused by colon cancer in a young adult has been reported; however, no genetic examination was performed for the diagnosis of Lynch syndrome [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. If a young person has colorectal cancer, close examination for Lynch syndrome should be performed.\u003c/p\u003e \u003cp\u003eAlthough the results of the genetic tests indicated the possibility of Lynch syndrome in this juvenile colon cancer case, the family history did not meet the Amsterdam and Bezesta criteria [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. We examined the immunohistochemical patterns and exome sequences of MLH1, MSH2, PMS2, and MSH6. IHC indicated the absence of MLH1 and PMS2 expression in the tumors. These data suggest the loss of MLH1 function because the expression of PMS2 depends on the availability of MLH1 function [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In contrast, genetic analysis of the peripheral blood and tumor revealed no pathological mutations in MLH1, MSH2, PMS2, or MSH6. Germline mutations in MMR-related genes cannot be identified in 10\u0026ndash;15% of patients with clinically suspected Lynch syndrome; thus, Lynch-like syndrome has been proposed for patients with colorectal cancer who are MSI-H but do not have germline mutations in MMR genes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. We suggest that this patient had MLH1 promoter methylation or MLH1 epimutation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLynch syndrome has been suggested to have a better prognosis than sporadic colorectal cancer. One reason for this is the low proportion of patients with advanced-stage Lynch syndrome. In stages I, II, and III, the survival rate of MSI-high colorectal cancer is significantly higher in stage I, II, and III microsatellite stable colorectal cancer [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, the patient did not receive adjuvant chemotherapy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe encountered a rare case of Lynch\u0026ndash;like syndrome in which the diagnosis was based on the onset of intussusception. MSI-high, wild-type BRAF, and the absence of MLH1 and PMS2 expression suggested Lynch syndrome. Additionally, there were no pathological mutations in the germline or somatic gene sequence. Hence, we suggest the possibility of MLH1 promoter methylation or MLH1 epimutation in the pathogenesis of this case.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMMR：mismatch repair\u003c/p\u003e\n\u003cp\u003eMSI：microsatellite instability\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBRAF：v-raf murine sarcoma viral oncogene homolog B1\u003c/p\u003e\n\u003cp\u003eKRAS：v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog\u003c/p\u003e\n\u003cp\u003eCT：Computed tomography\u0026nbsp;\u003c/p\u003e\n\u003cp\u003esIL2R：soluble interleukin-2 receptor\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCEA：carcinoembryonic antigen\u003c/p\u003e\n\u003cp\u003eCA19-9：carbohydrateantigen 19-9\u003c/p\u003e\n\u003cp\u003eGIST： gastrointestinal stromal tumor\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese analyses were conducted according to the Declaration of Helsinki and was approved by the Institutional Ethics Review Boards of Shunan Memorial Hospital (04-07) and Yamaguchi University (approval no. H17-83).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patients for publication of this report and any accompanying analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed for this study are included in this published\u003c/p\u003e\n\u003cp\u003earticle.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRO, TF, and SH performed the treatment of the patient. RO, SH, and KH collected the clinical data and wrote the manuscript. SH, RO, KH, RT, HN, TN applied and assessed the results of genetic examination and discussed the obtained results. TI, TK, RO, and SH applied and assessed the results of immunohistochemical examination and discussed the obtained results. All authors attended the discussion, and all authors have read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eNagorney DM, Sarr MG, McIlrath DC: \u003cstrong\u003eSurgical management of intussusception in the adult\u003c/strong\u003e. \u003cem\u003eAnn Surg\u0026nbsp;\u003c/em\u003e1981, \u003cstrong\u003e193\u003c/strong\u003e:230-236.\u003c/li\u003e\n \u003cli\u003eSiow SL, Chea CH, Hashimah AR, Ting SC: \u003cstrong\u003eAdult intussusception: 5-year experience in Sarawak\u003c/strong\u003e. \u003cem\u003eMed J Malaysia\u0026nbsp;\u003c/em\u003e2011, \u003cstrong\u003e66\u003c/strong\u003e:199-201.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ehttps://ganjoho.jp/reg_stat/statistics/data/dl/index.html#a14\u003c/strong\u003e. 2015.\u003c/li\u003e\n \u003cli\u003eLynch HT, de la 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Kajiwara Y, Konishi D, Tabuchi M, Aoyama K, Nogami T\u003cem\u003e\u0026nbsp;et al\u003c/em\u003e: \u003cstrong\u003e[A Case of Intussusception Caused by Colon Cancer in A 25-Year-Old Woman]\u003c/strong\u003e. \u003cem\u003eGan To Kagaku Ryoho\u0026nbsp;\u003c/em\u003e2017, \u003cstrong\u003e44\u003c/strong\u003e:1248-1250.\u003c/li\u003e\n \u003cli\u003eAbildgaard AB, Nielsen SV, Bernstein I, Stein A, Lindorff-Larsen K, Hartmann-Petersen R: \u003cstrong\u003eLynch syndrome, molecular mechanisms and variant classification\u003c/strong\u003e. \u003cem\u003eBr J Cancer\u0026nbsp;\u003c/em\u003e2023, \u003cstrong\u003e128\u003c/strong\u003e:726-734.\u003c/li\u003e\n \u003cli\u003eKang SY, Park CK, Chang DK, Kim JW, Son HJ, Cho YB, Yun SH, Kim HC, Kwon M, Kim KM: \u003cstrong\u003eLynch-like syndrome: characterization and comparison with EPCAM deletion carriers\u003c/strong\u003e. \u003cem\u003eInt J Cancer\u0026nbsp;\u003c/em\u003e2015, \u003cstrong\u003e136\u003c/strong\u003e:1568-1578.\u003c/li\u003e\n \u003cli\u003eZyla R, Graham T, Aronson M, Velsher L, Mrkonjic M, Turashvili G: \u003cstrong\u003eMLH1 epimutation is a rare mechanism for Lynch syndrome: A case report and review of the literature\u003c/strong\u003e. \u003cem\u003eGenes Chromosomes Cancer\u0026nbsp;\u003c/em\u003e2021, \u003cstrong\u003e60\u003c/strong\u003e:635-639.\u003c/li\u003e\n \u003cli\u003eStigliano V, Assisi D, Cosimelli M, Palmirotta R, Giannarelli D, Mottolese M, Mete LS, Mancini R, Casale V: \u003cstrong\u003eSurvival of hereditary non-polyposis colorectal cancer patients compared with sporadic colorectal cancer patients\u003c/strong\u003e. \u003cem\u003eJ Exp Clin Cancer Res\u0026nbsp;\u003c/em\u003e2008, \u003cstrong\u003e27\u003c/strong\u003e:39.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Lynch syndrome, microsatellite instability, BRAF, juvenile colon cancer, intussusception, laparoscopic colectomy","lastPublishedDoi":"10.21203/rs.3.rs-2725014/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2725014/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: One characteristic of Lynch syndrome, which is caused by germline mutations in a group of genes encoding mismatch repair proteins, is the early onset of colorectal cancer. Here, we report a rare case of juvenile colon cancer, diagnosed based on the onset of intussusception with high microsatellite instability (MSI) and the absence of BRAF mutations, which was suggestive of Lynch syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e: A 28-year-oldman presented with right lower abdominal pain for approximately 3 months and defecated blacky stool for several weeks. He visited our hospital because of increasingly intense right lower abdominal pain. Computed tomography revealed a contrast-enhanced tumor and lymph nodes with a crab-claw-like fitted image extending into the ascending colon. Colon endoscopy revealed a large submucosal tumor-like lesion with ulceration. Laparoscopy-assisted ileal resection with level 3 lymph node dissection was performed 3 days after the endoscopic reduction of the intussusception. The histological diagnosis was a poorly differentiated adenocarcinoma. Gene analysis of the resected tumor revealed high MSIand KRAS mutations, and the absence of BRAF mutations. Immunohistochemistry indicated the absence of MLH1 and PMS2 expression in tumors. Genetic analysis of peripheral blood and tumors revealed no pathological mutations in MLH1, MSH2, PMS2, or MSH6.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA rare case of Lynch-like syndrome was diagnosed with intussusception. MSI-high, wild-type BRAF, and the absence of MLH1 and PMS2 expression suggested Lynch syndrome. The absence of pathological mutations in germline and somatic genes suggests the possibility of MLH1 promoter methylation or MLH1 epimutation in the pathogenesis of this case.\u003c/p\u003e","manuscriptTitle":"Juvenile colon cancer diagnosed by onset of intussusception: a case report suggestive of Lynch syndrome treated with laparoscopic colectomy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-31 21:41:14","doi":"10.21203/rs.3.rs-2725014/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d7e7e68a-ca6c-44fd-8fb3-eb0be550208e","owner":[],"postedDate":"March 31st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-03-31T21:41:16+00:00","versionOfRecord":[],"versionCreatedAt":"2023-03-31 21:41:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2725014","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2725014","identity":"rs-2725014","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}